Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating disease that affects the central nervous system. In MS, it is believed that infiltrating inflammatory immune cells are involved in the destruction of oligodendrocytes, which are the cells responsible for creating and maintaining a fatty layer, known as the myelin sheath. MS results in the thinning or complete loss of myelin. When the myelin is lost, the neurons can no longer effectively conduct their electrical signals leading to numerous neurologic dysfunctions. Individuals with MS produce autoreactive T cells that participate in the formation of inflammatory lesions along the myelin sheath of nerve fibres. The cerebrospinal fluid of patients with active MS contains activated T cells, which infiltrate the brain tissue and cause characteristic inflammatory lesions, destroying the myelin. While the multiple sclerosis symptoms and course of illness can vary from person to person, there are three principle forms of the disease—relapsing-remitting MS, secondary progressive MS, and primary progressive MS.
In the early stages of MS, inflammatory attacks occur over short intervals of acutely heightened disease activity. These episodes are followed by periods of recovery and remission. During the remission period, the local swelling in the nervous system lesion resolves, the immune cells become less active or inactive, and the myelin-producing cells remyelinate the axons. Nerve signalling improves, and the disability caused by the inflammation becomes less severe or goes away entirely. This phase of the disease is called relapsing-remitting MS (RRMS). The lesions do not all heal completely, though. Some remain as “chronic” lesions, which usually have a demyelinated core region which lacks immune cells. Over time, the cells in the centre of such lesions mostly die, although inflammation often continues at their edges. The brain can adapt well to the loss of some neurons, and permanent disability may not occur for many years. However, more than 50% of patients with MS eventually enter a stage of progressive deterioration, called secondary progressive MS (SPMS). In this stage, the disease no longer responds well to disease-modifying drugs, and patients' disabilities steadily worsen. The destruction of neurons from early in the natural course of MS suggests that the progressive disabilities of SPMS might be the result of an accumulated neuronal loss that eventually overwhelms the brain's compensatory abilities. Primary progressive MS is a type of multiple sclerosis where there are no relapses, but over a period of years, there is gradual loss of physical and cognitive functions.
The goal of treatment in patients with relapsing-remitting multiple sclerosis is to reduce the frequency and severity of relapses (and thereby prevent exacerbations) as well as to prevent or postpone the onset of the progressive phase of the disease. To achieve this goal, in the past especially, immunomodulatory or immunosuppressive drugs have been used, but they have never found widespread acceptance owing to limited efficacy and considerable toxicity. For example, large randomized controlled trials have been performed successfully with interferon beta-1a, interferon beta-1 b, and glatiramer acetate.
Both altered autoimmune T cell responses and dysfunction of the regulatory network of the immune system play an important role in human autoimmune pathologies, such as MS and rheumatoid arthritis (Kuchroo et al., (2002) Annu. Rev. Immunol. 20:101-123; Sospedra and Martin (2005) Annu. Rev. Immunol. 23: 683-747; Toh and Miossec (2007) Curr. Opin. Rheumatol. 19:284-288).
Although the aetiology and pathogenesis of MS remain unknown, it is generally considered an autoimmune pathology in which autoreactive T cells of pathogenic potential, such as TH1 and TH17 cells, are thought to play an important role. There is evidence that these effector T cells are activated in vivo during the disease process and are attributable to the central nervous system (CNS) inflammation. There is also evidence that these T cells mediate destruction of myelin-expressing cells in lesions of EAE and MS during the active phase of the disease. On the other hand, regulatory T cells (Treg) that normally keep pathogenic TH1 and TH17 cells in check are deficient in patients with MS, further tilting the immune system toward an pro-inflammatory state.
Three separate groups recently reported the results of genome wide single nucleotide polymorphisms (SNPs) scanning in a total of 17,947 donors with or without MS. After scanning 334,923 SNPs, they found a highly significant association (overall P=2.9×10−7) of a nonsynonymous coding SNP in the human IL-7 receptor alpha chain (IL-7Rα) with MS susceptibility. The SNP corresponds to a change from T to C in exon 6 of CD127 (also known as IL-7Rα). This change enhances the chance of exon 6 skipping during RNA splicing, resulting in a soluble form of CD127. Furthermore, expressions of CD127 and IL-7 RNAs in the cerebrospinal fluids (CSFs) of MS patients are significantly higher relative to CSFs of patients with other neurological disorders.
IL-7 and IL-7 receptor (IL-7R) are known to play an important role in T cell and B cell development and homeostasis mainly in a thymic environment. Indeed, thymic stromal cells, fetal thymus, and bone marrow are sites of IL-7 of production. The IL-7 receptor consists of two subunits, CD127 and a common chain (gamma chain or yc) which is shared by receptors of IL-2, IL-4, IL-9, IL-15, and IL-21.
CD127 is also known as IL-7 receptor alpha (IL-7Rα) and p90 IL-7R. Human CD127 (Swiss Prot accession number P16871) has a total of 459 amino acids (20 signal sequence). It comprises a 219 amino acid extra cellular region, a 25 amino acid transmembrane region and a 195 amino acid intracellular region. The numbering of residues within CD127, as used herein (e.g. for the description of antibody epitopes) is based on the full length protein, including signal sequence residues. CD127 may exist in four isoforms, the isoform H20 (Swissprot accession number P16871-1) has the following amino acid sequence (including signal sequence):
(SEQ ID NO: 1)MTILGTTFGM VFSLLQVVSG ESGYAQNGDL EDAELDDYSFSCYSQLEVNG SQHSLTCAFE DPDVNTTNLE FEICGALVEV KCLNFRKLQE IYFIETKKFLLIGKSNICVK VGEKSLTCKK IDLTTIVKPE APFDLSVIYR EGANDFVVTF NTSHLQKKYVKVLMHDVAYR QEKDENKWTH VNLSSTKLTL LQRKLQPAAM YEIKVRSIPD HYFKGFWSEWSPSYYFRTPE INNSSGEMDP ILLTISILSF FSVALLVILA CVLWKKRIKP IVWPSLPDHKKTLEHLCKKP RKNLNVSFNP ESFLDCQIHR VDDIQARDEV EGFLQDTFPQ QLEESEKQRLGGDVQSPNCP SEDVVVTPES FGRDSSLTCL AGNVSACDAP ILSSSRSLDC RESGKNGPHVYQDLLLSLGT TNSTLPPPFS LQSGILTLNP VAQGQPILTS LGSNQEEAYV TMSSFYQNQ
CD127 is also found in the receptor of thymic stromal derived lymphopoietin (TSLP). The TSLP receptor is a heterodimer of CD127 and cytokine receptor-like factor 2 (CRLF2).
Binding of IL-7 to the IL-7R activates multiple signalling pathways including the activation of JAK kinases 1 and 3 leading to the phosphorylation and activation of Stat5. This pathway is crucial to the survival of thymic developing T cell precursors because Stat5 activation is required in the induction of the anti-apoptotic protein Bcl-2 and the prevention of the pro-apoptotic protein Bax entry into the mitochondrion. Another IL-7R mediated pathway is the activation of PI3 kinase, resulting in the phosphorylation of the pro-apoptotic protein Bad and its cytoplasm retention. CD127 is expressed in peripheral resting and memory T cells. The mechanism of IL-7 regulation of T cell survival and homeostasis and the source of IL-7 in the periphery are not completely understood. Furthermore, its potential role in the differentiation and function of pathogenic T cells in autoimmune disease is poorly studied and largely unknown. There are few reports suggesting that IL-7 may contribute to the pathogenesis of autoimmune diseases.
Recently, Liu and colleagues (Liu et al, (2010) Nature Medicine 16:191-197) have described the role of IL-7 in TH17 survival and expansion. Murine anti-CD127 antibodies (including the anti-CD127 antibodies 1A11 and 6A3) and their role in the treatment of MS and other autoimmune diseases have been described in PCT application number PCT/US2009/053136.
It is desirable to isolate and develop further monoclonal antibodies that bind to and/or inhibit the biological effect of human CD127. Such antibodies may be therapeutically useful in the treatment of MS and other inflammatory and autoimmune diseases and disorders, particularly those in which pathogenic TH17 cells have been implicated.